Novel tetrahydronaphthalene and indane derivatives

ABSTRACT

Novel styryl-tetrahydromaphthalene and indane derivatives useful for treating neoplasms and dermatoses.

This is a division of application Ser. No. 07/049,916 filed May 15,1987, now U.S. Pat. No. 4,870,219.

SUMMARY OF INVENTION

The present invention is concerned with novel tetrahydronaphthalene andindane derivatives of the formula ##STR1## wherein X and Y is ##STR2##R¹ is fluorine, chlorine, iodine, o-bromo, m-bromo, lower-alkoxy,acyloxy, nitro, hydroxy, amino, lower-alkylamino, di-lower-alkylamino orphenyl; or lower alkyl in the o- or m-position; R² and R³ are hydrogen,lower-alkyl, trifluoromethyl or halogen with one of R² and R³ beinghydrogen, trifluoromethyl or lower-alkyl, R⁴ and R⁵ are hydrogen, alkyl,alkoxy or halogen; R⁶ is hydrogen, halogen, lower-alkyl or --OR⁷ ; R⁷ ishydrogen, lower-alkyl or acyl; R⁸ is hydrogen or lower-alkyl; m is awhole number of from 0 to 5; with the proviso that when m is O and Z is--CH₂ --CH₂ --, R⁶ is hydrogen; and with the exception of1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α-methylstyryl)naphthalene andits derivatives which are hydroxylated in the terminal phenyl ring.

The compound of formula I are useful as for combatting dermatoses aswell as neoplasmas.

DETAILED DESCRIPTION

The expression "lower" relates to groups with 1-6 C-atoms. Alkyl andalkoxy groups can be straight-chain or branched such as methyl, ethyl,propyl, isopropyl, butyl, and sec.-butyl and methoxy, ethoxy, propoxy,isopropoxy, butoxy and sec.-butoxy, respectively. Alkyl and alkoxygroups R⁴ and R⁵ preferably contain from 1 to 10 carbon atoms such asoctyl, nonyl, decyl and 2,2-dimethyloctyl and octyloxy, nonyloxy,decyloxy and 2,2-dimethyloctyloxy, respectively. Examples of acyloxygroups are alkanoyloxy groups, preferably loweralkanoyloxy groupscontaining from 2 to 6 carboratoms such as acetoxy, propionyloxy,butyryloxy, pivaloyloxy and caproyloxy; or aroyloxy groups such asbenzoyloxy, p-nitrobenzoyloxy and toluoyloxy; or aralkanoyloxy groupssuch as phenylacetoxy. Halogen embraces fluorine, chlorine, bromine andiodine.

The compounds of formula I can exist as trans or cis isomers or ascis/trans isomer mixtures. In general, the trans compounds of formula Iare preferred.

Of the compounds of formula I there are furthermore preferred those inwhich X and Y is a group --C(CH₃)₂ -- and those in which m=1 or 2 or 3,especially 1. With respect to the substitutents R² and R³, hydrogen ispreferred for R² and lower-alkyl, especially methyl, is preferred forR³. R⁴ is preferably hydrogen or alkyl or alkoxy with up to 10 C-atoms.R⁵ and R⁶ are preferably hydrogen.

Among the preferred compound of formula I are the following compounds:

Compounds of the formula: ##STR3## wherein n is an integer of from 1 to3, R², R³, R⁴ and R⁵ are as above,; R¹¹, R¹², R¹³, and R¹⁴ are hydrogenor methyl, R¹⁰ is fluorine, chlorine, iodine, o-bromo or meta-bromo; andR¹⁵ is hydrogen, oxo, lower alkyl, acyloxy, hydroxy or lower alkoxy: and

Compounds of the formula: ##STR4## wherein n, R², R³, R⁴, R⁵, R¹⁰, R¹¹,R¹², R¹³, and R¹⁴ are as above; R¹⁶ and R¹⁷ are hydrogen, oxo, loweralkyl, acyloxy, hydroxy, or lower alkoxy with the proviso that both R¹⁶and R¹⁷ are not oxo;

Compounds of the formula: ##STR5## wherein n, R², R³, R⁴, R⁵, R¹¹, R¹²,R¹³, R¹⁴, R¹⁶ and R¹⁷ are as above; and

Compounds of the formula: ##STR6## wherein n, R², R³, R⁴, R⁵, R¹¹, R¹²,R¹³, R¹⁴, R¹⁶ and R¹⁷ are as above; with the proviso that when R³ ismethyl and R⁴ is hydrogen, at least one of R¹¹, R¹², R¹³ or R¹⁴ ishydrogen;

Compounds of the formula: ##STR7## wherein n, R², R³, R⁴, R⁵, R¹¹, R¹²,R¹³, R¹⁴, R¹⁶ and R¹⁷ are as above; and R¹⁸ is lower alkyl with at leastone lower alkyl group located in the ortho or meta positions:

Compounds of the formula: ##STR8## wherein n, R², R³, R⁴, R⁵, R¹¹, R¹²,R¹³, R¹⁴, R¹⁶ and R¹⁷ are as above; and R²⁵ is nitro, amino or loweralkylamino;

Compounds of the formula: ##STR9## wherein n, R², R³, R⁴, R⁵, R¹¹, R¹²,R¹³, R¹⁴, and R¹⁵ are as above; and R³⁵ is hydroxy, lower alkoxy oracyloxy; and

Compounds of the formula: ##STR10## wherein n, R², R³, R⁴, R⁵, R¹¹, R¹²,R¹³, R¹⁴, and R¹⁶ and R¹⁷ are as above; and R³³ is lower alkoxy oracyloxy; and

Compounds of the formula: ##STR11## wherein n, R², R³, R⁴, R⁵, R¹¹, R¹²,R¹³ and R¹⁴ are as above; and R²⁷ and R²⁸ are oxo, acyloxy, hydroxy, orlower alkoxy with the proviso that R²⁷ and R²⁸ are not both oxo.

The invention is also concerned with a process for the manufacture ofthe compounds of formula I, pharmaceutical preparations based on thecompounds of formula I, the compounds of formula I in the treatment andprophylaxis of neoplasms and dermatoses as well as the use of thecompounds of formula I in the manufacture of pharmaceutical preparationsfor the treatment and prophylaxis of such conditions.

The compounds of formula I can be manufactured in accordance with theinvention by reacting a compound of the general formula ##STR12## with acompound of the general formula ##STR13## in which either A is a residue--CH(R³)P⁺ (Q)₃ Y⁻ or --CH(R³)P(O)(OAlk)₂ and B is a residue R²¹ --CO--;or A is a residue R³¹ --CO-- and B is a residue --CH(R²)P⁺ (Q)₃ Y⁻ or--CH(R²)P(O)(OAlk)₂ or --CH(R²¹)MgHal; or A is a residue --CH(R³¹)MgHaland B is a residue R² --CO--; whereby in the above formulae Q is aryl;Y⁻ is the anion of an organic or inorganic acid; Alk is a lower alkylgroup; Hal is halogen; R²¹ and R³¹ are hydrogen, trifluoromethyl orlower-alkyl; and R¹, R², R³, R⁴, R⁵, X, Y, Z and m have the significancegiven above and the manufacture of1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α-methylstyryl)naphthalene andits derivatives which are hydroxylated in the terminal phenyl ring isexcluded, whereupon, if desired, a nitro group R¹ is reduced to theamino group, if desired an amino group R¹ is mono- or di-alkylated, ifdesired an acyloxy group R¹ or R⁷ is saponified, a carbonyl groupobtained in Z is reduced to the hydroxy group and, if desired, a hydroxygroup R¹ or R⁷ or a hydroxy group obtained in Z is alkylated oracylated.

The reaction of the compounds of formulae II and III can be carried outaccording to the known methods of the Wittig, Horner or Grignardreaction.

In the case of the Wittig reaction, i.e. with the use of a compound offormula II with A=--CH(R³)P⁺ (Q)₃ Y⁻ or of formula III with B=--CH(R²)P⁺(Q)₃ Y⁻, the components are reacted with one another in the presence ofan acid-binding agent, e.g. in the presence of a strong base such ase.g. butyl-lithium, sodium hydride or the sodium salt of dimethylsulphoxide, but especially in the presence of an optionally loweralkyl-substituted ethylene oxide such as 1,2-butylene oxide, optionallyin a solvent, e.g. in an ether such as diethyl ether or tetrahydrofuranor in an aromatic hydrocarbon such as benzene, in a temperature rangelying between room temperature and the boiling point of the reactionmixture.

Of the inorganic acid ions Y⁻ the chloride ion, the bromide ion or thehydrosulphate ion is preferred and of the organic acid ions the tosyloxyion is preferred. The aryl residue Q is preferably a phenyl residue or asubstituted phenyl residue such as p-tolyl.

In the case of the Horner reaction, i.e. with the use of a compound offormula II with A=--CH(R³)--P(O)(OAlk)₂ or of formula III withB=--CH(R²)--P(O)(OAlk)₂, the components are condensed with the aid of abase and preferably in the presence of an inert organic solvent, e.g.with the aid of sodium hydride in benzene, toluene, dimethylformamide,tetrahydrofuran, dioxan or 1,2-dimethoxyethane, or also with the aid ofa sodium alcoholate in an alkanol, e.g. sodium methylate in methanol, ina temperature range lying between 0° and the boiling point of thereaction mixture.

The alkoxy residues OAlk are especially lower alkoxy residues with 1-6carbon atoms such as methoxy or ethoxy.

The reaction of a compound of formula II with A=--CH(R³¹)MgHal or offormula III with B=--CH(R²¹)MgHal can be carried out in a manner knownper se under the conditions of a Grignard reaction, e.g. in an ethersuch as diethyl ether or tetrahydrofuran at room temperature andsubsequent water-cleavage with acidic agents, e.g. with organic acidssuch as p-toluenesulphonic acid.

Compounds of formula I which contain an amino group in the phenyl ring(i.e. in which a residue R¹ is amino) are conveniently manufactured viathe corresponding nitro compounds. A nitro group present in a compoundof formula I can be converted into an amino group in a manner known perse by reduction, e.g. with nascent hydrogen. An amino group present in acompound I can be mono- or di-alkylated in a manner known per se, e.g.by treatment with alkylating agents such as alkyl halides or alkylsulphates or by reductive alkylation with aldehydes such as formaldehydeor acetaldehyde and sodium cyanoborohydride. The reduction of a carbonylgroup contained in Z as well as the alkylation and acylation of hydroxygroups can also be carried out in a manner known per se. For example, acarbonyl group can be reduced to the hydroxy group by treatment withreduction agents such as sodium borohydride.

The compounds of formula I can exist in trans or cis form. In theprocess they are mainly obtained in the trans form. Cis components whichmay be obtained can be separated, if desired, in a manner known per se.

The starting materials of formulae II and III, insofar as theirpreparation is not known or is not described hereinafter, can beprepared in analogy to known methods or to methods describedhereinafter.

The compounds of formula I are therapeutically active. In particular,they possess antiseborrhoeic, anti-keratinizing, anti-neoplastic andanti-allergic/anti-inflammatory activity, which can be demonstratedusing the test procedures described hereinafter:

(A) The antikeratinizing activity can be determined on the rhino mousemodel according to the following procedure. The skin of the rhino mouseis characterized by the presence of keratin-filled utriculi of theepidermis and subcutaneous cysts, both of which are derived from hairfollicles. The administration of retinoids leads to a hyperproliferationof the epidermis and of the epithelial lining of the utriculi. Thethickening of the epidermis and the reduction in the size of theutriculi lead to a normalization of the altered structure of theepithelial layer. The daily topical application of 0.1 ml/cm² skin ofthe rhino mouse of a 3% acetone solution of an active test compound overa period of 3 weeks or the thrice weekly oral administration in arachisoil over a period of 3 weeks leads to a significant proliferation of theepidermis and a striking reduction of the keratin-filled utriculi.

(B) The activity in the prevention of chemically-induced breast tumourscan be determined according to the following procedure. FemaleSprague-Dawley rats are kept under temperature-controlled andlight-controlled conditions, with free access to drinking water andfeed. At the age of 50 days 15 mg of dimethylbenz(a)anthracene disolvedin arachis oil are administered to each rat by means of a probang. Thetreatment with the test compounds begins 1 day after the administrationof the carcinogen. The body weights of the test animals are recorded andthe tumours are palpated weekly and measured with a vernier caliper. Thevolumes are calculated according to the formula ##EQU1##

in which D is the larger diameter of the tumour ellipsoid and d is thesmaller diameter of the tumour ellipsoid. After 11 weeks the test isterminated and evaluated. In this test there are used in addition to 30control animals, which receive exclusively normal feed, the followingtwo groups of test animals:

1. 33 rats to which are administered daily 30 mg/kg of test compoundmixed with the feed.

2. 36 rats to which are administered daily 90 mg/kg of test compoundmixed with the feed.

(C) Furthermore, the activity on tumours can be determined on thetransplantable chondrosarcoma of the rat according to the followingmethod. The solid tumour of a donor animal is finely minced andsuspended in phosphate buffer/sodium chloride solution. 0.5 ml of the30% tumour suspension is implanted subcutaneously into albino rats.

The transplanted rats are divided into test groups of in each case 8animals. The test compounds are suspended in arachis oil andadministered orally five times per week for 24 days. The tumours areexcised and weighted on day 24. The results are expressed in thequotient C/T which is calculated as follows: ##EQU2##

(D) The antimetaplastic activity can also be determined in ratsaccording to the following method. Female Holtzmann rats weighingapproximately 100 g are ovarectomized under Thiogenal narcosis after anadaptation period of 8 days and are used in the test after a further 14days. In each case two animals are placed in a cage with free access tofeed which contains approximately 2000 IU of vitamin A determinedanalytically. Prior to the oral administration of the test compound theanimals are treated subcutaneously each day on 6 successive days with 1μg of estradiol benzoate and 250 μg of testosterone propionate dissolvedin 0.1 ml of sesame oil. The parenteral hormone administration leads tothe formation of a clear granular stage in the vaginal smear, i.e. asquamous metaplasia. 2 days after the oral administration of the testsubstance the result of the reaction is again read off on the vaginalepithelium. The area method according to Behrens and Karber is employedto calculate the average effective dosages.

(E) The activity of the compounds I on sebum secretion in rats wasdetermined according to the following procedure. Male rates ofapproximately 50-60 g body weight were castrated at the age of 21-22days. One week after this operation the rats were washed in a cleansingsolution in order to remove sebum which was excreted prior to the testperiod. Only the carrier materials used were administered to one groupof rats. A further group of rats also simultaneously received 100 μg oftestosterone propionate in 0.2 ml of sesame oil per rat and day. To afurther group of rats there were administered daily per rat 100 μg oftestosterone propionate in 0.2 ml of sesame oil subcutaneously and thetest compounds in various dosages in 0.2 ml of propylene glycol orally.The rats were thus-treated for 14 days. On the 15th day the sebum fromthe skin surface and the pelt was removed by immersing the entire bodyof the test animals in a determined volume of acetone and bathingtherein for 2 minutes. An aliquot of the solvent bath was evaporated andthe solid residue was determined gravimetrically. The inhibition of thetestosterone-stimulated increase in the serum secretion in comparison tothe corresponding values from rats treated only with testosteronepropionate was used as the measurement for the activity.

The results of these tests A-E with compounds of formula I are presentedin Tables I-V hereinafter.

                  TABLE I    ______________________________________    (A) Anti-keratinizing activity in the rhino mouse              Dosage     Diameter of the              [mg/kg]    utriculus   Reduction    Compound  p.o.       [μm]     [%]    ______________________________________    a          0         151              400        117         21    b          0         161              400        131         19    c          0         125              133         91         27              400         61         51    d          0         168              133        125         27    ______________________________________

                  TABLE II    ______________________________________    (B) Prophylaxis of chemically-induced breast tumours                               Average Average                               number of                                       tumour            Dosage   Rats with tumours per                                       volume per            [mg/kg]  tumours [%                               rat [% of                                       rat in mm.sup.3    Compound            p.o.     of controls]                               controls]                                       [% of controls]    ______________________________________    a       30       72        47      22            90       69        42      22    b       30       106       87      90            90       99        87      43    c       30       92        56      78            90       85        43      32    ______________________________________

                  TABLE III    ______________________________________    (C) Activity on transplatable chondrosarcoma of the rat                       Quotient C/T of tumour weight              Dosage   of the untreated control              [mg/kg]  animals and of the treated    Compound  p.o.     animals    ______________________________________    b         120      1.6    c          40      2.0              120      24.0    f         120      1.6    ______________________________________

                  TABLE IV    ______________________________________    (D) Antimetaplastic activity in the rat    Compound         Relative activity    ______________________________________    all-Trans-retinoic acid                     1    a                0.87    b                0.77    c                1.04    ______________________________________

                  TABLE V    ______________________________________    (E) Inhibition of sebum production in the rat               Dosage   Inhibition of testosterone-               [μg/rat]                        stimulated sebum secretion    Compound   p.o.     [%]    ______________________________________    a          100      67    b          100      65    e          100      71    g          100      71    ______________________________________

a:(E)-6-(p-Fluoro-α-methylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene

b:(E)-6-(p-Bromo-α-methylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene

c:1,2,3,4-Tetrahydro-6-[(E)-p-methoxy-α-methylstyryl]-1,1,4,4-tetramethylnaphthalene

d: 1,1,3,3-Tetramethyl-5-[(E)-α-methylstyryl]indane

e:(E)-6-(p-Iodo-α-methylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene

f:(E)-6-(p-Chloro-α-methylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene

g:1,2,3,4-Tetrahydro-1,1,4,4-tetramethyl-6-(α-methylstyryl)-7-octylnaphthalene.

The compounds of formula I can be used for the topical and systemictherapy of benign and malignant neoplasms, of premalignant lesions andalso for the systemic and topical prophylaxis of the said conditions.

Furthermore, they are suitable for the topical and systemic therapy ofacne, psoriasis and other dermatoses which are accompanied by anintensified or pathologically altered cornification, as well as ofinflammatory and allergic dermatological conditions. Further, thecompounds of formula I can also be used for the control of mucousmembrane disorders with inflammatory or degenerative or metaplasticchanges.

The pharmaceutical preparations can be administered enterally,parenterally or topically. For enteral administration there are suitablee.g. preparations in the form of tablets, capsules, dragees, syrups,suspensions, solutions and suppositories. Preparations in the form ofinfusion or injection solutions are suitable for parenteraladministration.

The dosages in which the preparations are administered can varyaccording to the mode of use and route of use as well as according tothe requirements of the patients. In general, daily doses of about0.1-50 mg/kg, preferably 1-15 mg/kg, come into consideration for adults.

The preparations can be administered in one dosage or several dosages.Capsules containing about 5-200 mg of active substance are a preferredadministration form.

The preparations can contain inert or pharmacodynamically activeadditives. Tablets or granulates e.g. can contain a series of bindingagents, filler materials, carrier substances or diluents. Liquidpreparations can be present, for example, in the form of a sterilesolution which is miscible with water. Capsules can contain a fillermaterial or thickening agent in addition to the active substance.Furthermore, flavour-improving additives as well as the substancesusually used as preserving, stabilizing, moisture-retaining andemulsifying agents, salts for varying the osmotic pressure, buffers andother additives can also be present.

The previously mentioned carrier substances and diluents can be organicor inorganic substances, e.g. water, gelatine, lactose, starch,magnesium stearate, talc, gum arabic, polyalkylene glycols and the like.It is a prerequisite that all adjuvants used in the manufacture of thepreparations are non-toxic.

For topical use the active substances are conveniently used in the formof salves, tinctures, creams, solutions, lotions, sprays, suspensionsand the like. Salves and creams as well as solutions are preferred.These preparations intended for topical use can be manufactured bymixing the compounds of formula I as active ingredients with non-toxic,inert, solid or liquid carriers which are usual in such preparations andwhich are suitable for topical treatment.

For topical use there are suitable conveniently about 0.1-5%, preferably0.3-2%, solutions as well as about 0.1-5%, preferably about 0.3-2%,salves or creams.

If desired, the pharmaceutical preparations can contain an antioxidant,e.g. tocopherol, N-methyl-γ-tocopheramine, butylated hydroxyanisole orbutylated hydroxytoluene.

The following Examples illustrate the invention further. Thetemperatures are given in degrees Celsius.

EXAMPLE 1

45 g of[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphoniumbromide are suspended in 200 ml of 1,2-butylene oxide. After theaddition of 8 g of 4-fluorobenzaldehyde the mixture is boiled at refluxfor 16 hours. After cooling the clear, yellowish solution is poured into1 l of methanol/water (6:4) and extracted repeatedly with hexane. Theorganic phase is washed three times with water and, after drying oversodium sulphate, evaporated. The crystalline residue can berecrystallized from hexane and gives 11.2 g of(E)-6-(p-fluoro-α-methylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalenein colourless crystals, melting point 99°-101°.

In an analogous manner there are obtained

(E)-6-[p-chloro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene,melting point 125°-126°;

(E)-6-[p-iodo-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene,melting point 124°-126°;

(E)-6-[p-nitro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene,melting point 164°-165°;

(E)-6-[2-(4-biphenylyl)-1-methylvinyl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene,melting point 127°-128°;

(E)-6-[m-fluoro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene,melting point 72°-73°;

(E)-6-[m-bromo-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene,melting point 98°-99°;

(E)-6-[o-fluoro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene,melting point 75°-77°;

(E)-6-[o-bromo-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene,melting point 64°-66°;

1,1,3,3-tetramethyl-5-[(E)-α-methylstyryl]indane, melting point 48°-50°;

1,1,3,3-tetramethyl-5-[(E)-α-methyl-p-nitrostyryl]-indane, melting point149°-150°;

5-(p-fluoro-α-methylstyryl)-1,1,3,3-tetramethylindane, melting point75°-77°;

5-(p-chloro-α-methylstyryl)-1,1,3,3-tetramethylindane, melting point96°-98°;

5-(p-iodo-α-methylstyryl)-1,1,3,3-tetramethylindane, melting point129°-131°;

1,1,3,3-tetramethyl-5-[(E)-p-methoxy-α-methylstyryl]-indane, meltingpoint 83°-84°;

1,2,3,4-tetrahydro-1,1-dimethyl-6-(α-methylstyryl)-naphthalene, meltingpoint 46°-48° (from ethanol);

1,2,3,4-tetrahydro-1,1-dimethyl-7-(α-methylstyryl)-naphthalene, meltingpoint 58°-59° (from ethanol);

7-[(E)-p-fluoro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene,melting point 64°-65° (from ethanol).

EXAMPLE 2

358 g of[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphoniumbromide are suspended in 600 ml of tetrahydrofuran and treated at 0°with 400 ml of n-butyllithium (1.6 molar in hexane). After stirring at0° for 30 minutes a solution of 78.5 g of p-methoxybenzaldehyde in 200ml of tetrahydrofuran is added dropwise thereto and the mixture isstirred at room temperature for a further 2 hours. The reaction mixtureis subsequently poured into 2 l of methanol/water (6:4) and extractedrepeatedly with hexane. The organic phase is washed three times withwater and, after drying with sodium sulphate, evaporated. Thecrystalline residue can be recrystallized from hexane and gives 138 g of1,2,3,4-tetrahydro-6-[(E)-p-methoxy-α-methylstyryl]-1,1,4,4-tetramethylnaphthalene,melting point 108°-110°.

In an analogous manner there are obtained

p-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylacetate, melting point 114°-116°;

m-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylacetate, melting point 83°-85°;

o-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenylacetate, melting point 78°-80°;

1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-1-(α,m-dimethylstyryl)naphthalene,melting point 106°;

1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α,o-dimethylstyryl)naphthalene,melting point 61°-62°;

1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α,3,5-trimethylstyryl)naphthalene,melting point 113°-114°;

1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α,2,5-trimethylstyryl)naphthalene,melting point 72°;

1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α,2,6-trimethylstyryl)naphthalene,melting point 78°.

EXAMPLE 3

6 g of6-[p-nitro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthaleneare dissolved in 200 ml of acetic acid and, after heating to 90°,treated within 2 minutes with 4.5 g of activated iron powder.Thereafter, 60 ml of water are added thereto and, after a further 30minutes, the mixture is again treated with 60 ml of water. Afterstirring at 90° for 1 hour the reaction mixture is cooled, diluted withwater and extracted with ether. The organic phase is washed with water,dilute soda solution and again with water. After drying with sodiumsulphate the organic phase is evaporated and there is obtained a brownoil which is purified by filtration over silica gel (elution agenthexane/acetic acid 4:1). Recrystallization from hexane gives 4.5 g ofp-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]anilinein colourless crystals, melting point 106°-108°.

EXAMPLE 4

320 mg ofp-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]anilineare dissolved in 5 ml of acetonitrile and treated at room temperaturewith 440 mg of acetaldehyde and 190 mg of sodium cyanoborohydride. After30 minutes the mixture is adjusted to a pH of 6-7 by the addition ofacetic acid and 440 mg of acetaldehyde are again added thereto. Afterstirring at room temperature for 2 hours the reaction mixture is pouredinto ice-water, made alkaline by the addition of 2N potassium hydroxidesolution and extracted with ether. The brownish oil obtained afterdrying and evaporation of the organic solvent is filtered over silicagel (elution agent hexane/ethyl acetate 9:1) and recrystallized fromhexane. There are obtained 280 mg ofN,N-diethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]anilinein colourless crystals, melting point 89°-90°.

EXAMPLE 5

6.1 g of (1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl) ethylketone are dissolved in 25 ml of abs. ether and added dropwise at 0° toa benzylmagnesium chloride solution prepared from 0.6 g of magnesium and4.3 g of benzyl chloride in 30 ml of abs. ether. After stirring at roomtemperature for 2 hours the reaction mixture is poured into a saturatedammonium chloride solution, extracted with ether, dried over sodiumsulphate and evaporated. The thus-obtained oil is dissolved in 100 ml oftoluene and, after the addition of 0.5 g of p-toluenesulphonic acid,boiled at reflux overnight. After cooling the mixture is treated with10% sodium bicarbonate solution, extracted with ether, dried andevaporated. The residue is purified by filtration over a short column(silica gel, elution agent hexane) and recrystallized from methylenechloride/methanol. There are obtained 3 g of6-(α-ethylstyryl)-1,2,3,5-tetrahydro-1,1,4,4-tetramethylnaphthalene incolourless crystals, melting point 65°.

EXAMPLE 6

1.1 g of sodium hydride (50% in mineral oil) are washed with abs.pentane, dried and suspended in 20 ml of dimethylformamide. Whilecooling with ice there is added dropwise thereto a solution of 5.3 g ofdiethyl benzylphosphonate in 50 ml of dimethylformamide. After 1 hour asolution of 5 g of 1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthylaldehyde in 40 ml of dimethylformamide is allowed to drop in and themixture is stirred at 40° overnight. The reaction mixture is poured onto ice, extracted repeatedly with ether, dried and evaporated. In orderto separate the Z-isomer, the thus-obtained oil is chromatographed(silica gel, elution agent hexane) and recrystallized from hexane. Thereare obtained 4.1 g of(E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-styrylnaphthalene incolourless crystals, melting point 57°-58°.

EXAMPLE 7

In analogy to Example 6, by the Wittig-Horner reaction of 6.8 g ofdiethyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)methanephosphonatewith 2.4 g of acetophenone there are obtained, after recrystallizationfrom methanol, 1.5 g of(E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(β-methylstyryl)naphthalenein colourless crystals, melting point 72°-73°.

The phosphonate used in this Example can be prepared in a simple mannerstarting from 1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl aldehydeby reduction with sodium borohydride in ethanol to the correspondinghydroxymethyl compound (melting point 78° from pentane), conversion intothe bromomethyl compound (boiling point 125°/0.01 mm) by reaction withphosphorus tribromide and reaction with triethyl phosphite (16 hours,150°, melting point 55° from hexane).

EXAMPLE 8

In analogy to Example 1, from 20 g of[1-(5,6,7,8-tetrahydro-2-naphthyl)ethyl]triphenylphosphonium bromide and4 g of benzaldehyde there are obtained, after chromatography (silicagel, elution agent hexane), 4.6 g of1,2,3,4-tetrahydro-6-(α-methylstyryl)naphthalene as a colourless oil,boiling point about 170°/0.01 mm.

EXAMPLE 9

A solution of diethyl benzylphosphonate in 30 ml of dimethylformamide isadded at room temperature to a suspension of 3.7 g of NaH (50% inmineral oil) in 50 ml of dimethylformamide. After stirring at roomtemperature for 15 minutes a solution of 12.6 g of7-acetyl-1,1,4,4,6-pentamethyltetralin in 60 ml of dimethylformamide isadded dropwise thereto in the course of 2 hours. The reaction mixture isstirred at room temperature overnight and subsequently heated to 60° fora further 1 hour. After cooling the mixture is poured on to ice,extracted with ether, dried and evaporated. After chromatography of thecrude product (silica gel, elution agent hexane) and crystallizationfrom hexane there are obtained 3.9 g of1,2,3,4-tetrahydro-1,1,4,4,7-pentamethyl-6-[(E)-α-methylstyryl]naphthalenein colourless crystals, melting point 75°-77°.

EXAMPLE 10

In analogy to Example 9, from diethyl benzylphosphonate and5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-octyl-2-acetonaphthone there ismanufactured1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α-methylstyryl)-7-octylnaphthalene,melting point 47°-48° (from hexane).

EXAMPLE 11

In analogy to Example 1, from 7.1 g of[1-(1,1,3,3-tetramethyl-indan-2-on-5-yl)ethyl]triphenylphosphoniumbromide and 1.4 g of benzaldehyde there are obtained, afterchromatography (silica gel, elution agent hexane/ether=9:1) andrecrystallization from hexane, 800 mg of1,1,3,3-tetramethyl-5-[(E)-α-methylstyryl]-2-indanone, melting point83°-85°.

The phosphonium bromide used as the starting material can be prepared ina simple manner by the Friedel-Crafts acetylation of1,1,3,3-tetramethylindanone, reduction of the acetyl group with sodiumborohydride and reaction with triphenylphosphonium bromide.

EXAMPLE 12

1.4 g of 1,1,3,3-tetramethyl-5-[(E)-α-methylstyryl]-2-indanone aredissolved in 100 ml of ethanol and treated at room temperature with 6 gof sodium borohydride. After stirring at room temperature for 16 hoursthe reaction mixture is poured on to ice and extracted repeatedly withether. The organic phase is washed with saturated sodium chloridesolution, dried and evaporated. The residue can be recrystallized fromhexane and gives 1.1 g of1,1,3,3-tetramethyl-5-[(E)-α-methylstyryl]-2-indanol in colourlesscrystals, melting point 63°-67°.

EXAMPLE 13

2.80 g of 6'-(tert-butyldimethylsiloxy)-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2-acetonaphthone in 10 ml of abs. THF are addeddropwise at 0° to a Grignard solution prepared from 1.90 g of benzylchloride and 437 mg of Mg shavings in 30 ml of abs. THF. After 15minutes the mixture is hydrolyzed with H₂ O, extracted with ether andthe organic phases are washed thoroughly with H_(i) O. After drying andremoving the solvent the residue, a viscous oil, is taken up in 20 ml ofCH₂ Cl₂ and treated with 150 mg of p-toluenesulphonic acid. After 6hours the mixture is filtered over silica gel and the crude product istreated at 40° for about 14 hours with 6.3 g of nBu₄ NF·3H₂ O in 20 mlof THF. The reaction product is partitioned between water and ether, andthe organic phase is washed with water, dried and evaporated. Filtrationover silica gel yields 2.27 g of an oil which contains all threepossible double bond isomers. In order to equilibrate this, the oil istreated with 200 mg of p-toluenesulphonic acid in 20 ml of CHCl₃ at45°-50°. After 24 hours it is chromatographed over a short silica gelcolumn (petroleum ether: AcOEt=7:3) and recrystallized from hexane. Asingle repetition of the isomerization with the mother liquor yields atotal of 1.32 g of1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6[(E)-α-methylstyryl]-2-naphthalenol,m.p. 102°-103°.

The starting material can be obtained as follows:

p-Bromophenylacetic acid is converted by double alkylation, conversioninto the acid chloride and tandem Friedel-Crafts reaction of the acidchloride with isobutylene under SnCl₄ or AlCl₃ catalysis into6-bromo-3,4-dihydro-1,1,4,4-tetramethyl-2(1H)-naphthalenone, from whichby NaBH₄ reduction and silylation with TBDMS Cl/imidazole there isobtained[(6-bromo-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-2-naphthyl)oxy]tert.-butyldimethylsilane.Grignard reaction with acetaldehyde and MnO₂ oxidation yields6'-(tert-butyldimethylsiloxy)-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2-acetonaphthone.

EXAMPLE 14

In analogy to Example 13, from benzylmagnesium chloride and7'-(tert-butyldimethylsiloxy)-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2-acetonaphthonethere is obtained1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-7-[(E)-α-methylstyryl]-2-naphthalenol,m.p. 89°-91°.

The starting material can be obtained as follows:

m-Bromobenzyl cyanide is converted by double alkylation and basichydrolysis into 2-(m-bromophenyl)-2-methylpropionic acid which isfurther converted in analogy to the process steps described in Example13 via 7-bromo-3,4-dihydro-1,1,4,4-tetramethyl-2(1H)-naphthalenone.

EXAMPLE 15

144 mg of a 50% sodium hydride dispersion are suspended in 3 ml ofdimethylformamide and treated with 740 mg of diethylfluorophenylmethanesulphonate (prepared from benzyl fluoride by radicalbromination with N-bromosuccinimide and reaction with triethylphosphite). After stirring at room temperature for 2 hours 1.15 g of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-acetonaphthone are addeddropwise thereto and the mixture is heated at 55° overnight. Aftercooling the mixture is poured into ice-water and extracted with ether.After drying and evaporating the organic phase there are obtained 1.3 gof crude product which is purified by chromatography on silica gel(elution agent hexane/ethyl acetate=99:1) and, after recrystallizationfrom hexane, there are obtained 77 mg of6-[(Z)-β-fluoro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene,m.p. 100°.

EXAMPLE 16

In analogy to Example 1, from 19.4 g of[1-(1,1,3,3-tetramethyl-5-indanyl)ethyl]triphenylphosphonium bromide,6.9 g of ethyl p-formylphenylcarbonate and 200 ml of butylene oxidethere are obtained, after filtration of the crude product over silicagel (elution agent hexane/ethyl acetate=19:1), 5 g of ethylp-[2-(1,1,3,3-tetramethyl-5-indanyl)propenyl]phenylcarbonate as ayellowish oil which solidifies in the cold and which can berecrystallized from hexane. 5 g of the thus-obtained product aredissolved in 50 mg of ethanol and treated with a solution of 7.4 g ofpotassium hydroxide in 25 ml of water. After stirring at roomtemperature for 3 hours the mixture is poured into ice-water, acidifiedwith 3N hydrochloric acid, extracted with ethyl acetate and evaporated.After recrystallization of the crude product from hexane there areobtained 2.6 g of p-[2-(1,1,3,3-tetramethyl-5-indanyl)propenyl]phenol incolourless crystals, m.p. 137°.

The ethyl p-formylphenylcarbonate used as the starting material can beprepared in a simple manner by reacting p-hydroxybenzaldehyde with ethylchloroformate with the addition of triethylamine. Distillation of thecrude product gives ethyl p-formylphenylcarbonate as a colourlessliquid, b.p. 111°-113°/2.5 mm.

EXAMPLE 17

In analogy to Example 1, from 21.9 g of[1-(1,1,3,3-tetramethyl-indan-2-on-5-yl)ethyl]triphenylphosphoniumbromide, 7.6 g of ethyl p-formylphenylcarbonate and 400 ml of butyleneoxide there are obtained, after filtration of the crude product oversilica gel (elution agent hexane/ethyl acetate=4:1) andrecrystallization from hexane/ethyl acetate, 3.4 g of ethylp-[2-(1,1,3,3-tetramethyl-2-oxo-5-indanyl)propenyl]phenylcarbonate, m.p.130°-131°.

Hydrolysis of this product with an excess of potassium hydroxide inethanol/water gives, after recrystallization from ethyl acetate/hexane,1.7 g of 5-(p-hydroxy-α-methylstyryl)-1,1,3,3-tetramethyl-2-indanone incolourless crystals, m.p. 172°-173°.

EXAMPLE 18

A solution of 1 g of5-(p-hydroxy-α-methylstyryl)-1,1,3,3-tetramethyl-2-indanone in 10 ml oftetrahydrofuran is added dropwise while cooling with ice to a suspensionof 100 mg of lithium aluminium hydride in 5 ml of tetrahydrofuran andthe mixture is subsequently left to stir at room temperature for 2hours. After the dropwise addition of 50 ml of 2N hydrochloric acid at0° the mixture is extracted with ethyl acetate and the organic phase iswashed with water, dried and evaporated. After filtration of the crudeproduct over silica gel (elution agent hexane/ethyl acetate=1:1) it isrecrystallized from ethyl acetate/hexane and there are obtained 500 mgof 5-(p-hydroxy-α-methylstyryl)-1,1,3,3-tetramethyl-2-indanol incolourless crystals, m.p. 148°-149°.

EXAMPLE 19

In analogy to Example 2, from[1-(5,6,7,8-tetrahydro-3-methoxy-5,5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphoniumbromide and ethyl p-formylphenylcarbonate there is obtained ethyl[p-[(E)-2-(5,6,7,8-tetrahydro-3-methoxy-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-phenyl]carbonatem.p. 122°-123°.

Hydrolysis of this product with an excess of potassium hydroxide inethanol/water gives, after recrystallization from methanol,p-[(E)-2-(5,6,7,8-tetrahydro-3-methoxy-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenol,m.p. 181°.

EXAMPLE 20

In analogy to Example 5,

from 7-acetyl-6-chloro-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthaleneand benzylmagnesium chloride there is obtained(E)-6-chloro-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-7-(α-methylstyryl)naphthalenem.p. 114°,

from7-acetyl-1,2,3,4-tetrahydro-6-methoxy-1,1,4,4-tetramethylnaphthalene andbenzylmagnesium chloride there is obtained(E)-1,2,3,4-tetrahydro-7-methoxy-6-(α-methylstyryl)-1,1,4,4-tetramethylnaphthalene,m.p. 88°-89°, and

from7-acetyl-1,2,3,4-tetrahydro-5,8-dimethoxy-1,1,4,4-tetramethylnaphthaleneand benzylmagnesium chloride there is obtained(E)-1,2,3,4-tetrahydro-5,8-dimethoxy-6-(α-methylstyryl)naphthalene, m.p.110°.

The manufacture of dosage forms of the compounds of formula I can beeffected in the usual manner, e.g. on the basis of the followingExamples.

EXAMPLE A

Hard gelatine capsules can be manufactured as follows:

    ______________________________________    Ingredients              mg/capsule    ______________________________________    1.    Spray-dried powder containing 75% of                                 200          compound I    2.    Sodium dioctyl sulphosuccinate                                 0.2    3.    Sodium carboxymethylcellulose                                 4.8    4.    Microcrystalline cellulose                                 86.0    5.    Talc                   8.0    6.    Magnesium stearate     1.0    Total                    300    ______________________________________

The spray-dried powder, which is based on the active substance, gelatineand microcrystalline cellulose and which has an average particle size ofthe active substance of <1μ (measured by means of autocorrelationspectroscopy), is moistened with an aqueous solution of sodiumcarboxymethylcellulose and sodium dioctyl sulphosuccinate and kneaded.The resulting mass is granulated, dried and sieved, and the granulateobtained is mixed with microcrystalline cellulose, talc and magnesiumstearate. The powder is filled into size 0 capsules.

EXAMPLE B

Tablets can be manufactured as follows:

    ______________________________________    Ingredients:            mg/tablet    ______________________________________    1. Compound I as a finely milled powder                            500    2. Lactose powd.        100    3. Maize starch white    60    4. Povidone K30          8    5. Maize starch white   112    6. Talc                  16    7. Magnesium stearate    4    Total                   800    ______________________________________

The finely milled substance is mixed with lactose and a portion of themaize starch. The mixture is moistened with an aqueous solution ofPovidone K30 and kneaded, and the resulting mass is granulated, driedand sieved. The granulate is mixed with the remaining maize starch, talcand magnesium stearate and pressed to tablets of suitable size.

EXAMPLE C

Soft gelatine capsules can be manufactured as follows:

    ______________________________________    Ingredients     mg/capsule    ______________________________________    1. Compound I    50    2. Triglyceride 450    Total           500    ______________________________________

10 g of compound I are dissolved in 90 g of medium-chain triglyceridewith stirring, inert gasification and protection from light. Thissolution is processed as the capsule fill mass to soft gelatine capsulescontaining 50 mg of active substance.

EXAMPLE D

A lotion can be manufactured as follows:

    ______________________________________    Ingredients:    ______________________________________    1. Compound I, finely milled                             3.0 g    2. Carbopol 934          0.6 g    3. Sodium hydroxide q.s. ad                             pH 6    4. Ethanol 94%           50.0 g    5. Demineralized water ad                             100.0 g    ______________________________________

The active substance is incorporated into the ethanol, 94%/water mixtureunder protection from light. Carbopol 934 is stirred in until gelling iscomplete and the pH value is adjusted with sodium hydroxide.

We claim:
 1. A compound of the formula: ##STR14## wherein R² and R³ arehydrogen, lower alkyl, trifluoromethyl or halogen, with one of R² and R³being hydrogen, lower alkyl or trifluromethyl; R⁵ is hydrogen, alkyl,alkoxy or halogen; R⁴ is alkyl, alkoxy, or halogen; R¹¹, R¹², R¹³ andR¹⁴ are methyl; and R¹⁵ and R¹⁶ are hydrogen, lower alkoxy, oxo, loweralkyl, acyloxy, or hydroxy; with the proviso that both R¹⁵ and R¹⁶ arenot oxo.
 2. The compound of claim 1 wherein said compound is1,2,3,4-tetrahydro-1,1,4,4,7-pentamethyl-6-[(E)-α-methylstyryl]naphthalene.3. The compound of claim 1 wherein said compound is1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α-methylstyryl)-7-octylnaphthalene.4. The compound of claim 1 wherein said compound is(E)-1,2,3,4-tetrahydro-7-methoxy-6-(α-methylstyryl)-1,1,4,4-tetramethylnaphthalene.5. The compound of claim 1 wherein said compound is(E)-6-chloro-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-7-(α-methylstyryl)naphthalene.6. The compound6-(α-ethylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene. 7.The compound(E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-styryl-naphthalene.